A novel leukemic route of mutant NPM1 through nuclear import of the overexpressed long noncoding RNA LONA

• Published in: Leukemia Vol. 35; no. 10; pp. 2784 - 2798
• Main Authors: Gourvest, Morgane, De Clara, Etienne, Wu, Hsin-Chieh, Touriol, Christian, Meggetto, Fabienne, De Thé, Hugues, Pyronnet, Stéphane, Brousset, Pierre, Bousquet, Marina
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 01.10.2021; Springer Nature; Nature Publishing Group UK
• Subjects: Active Transport, Cell Nucleus - genetics; Acute myeloid leukemia; Animal biology; Animals; Carcinogenesis - genetics; Cell differentiation; Cell Differentiation - genetics; Cell Line, Tumor; Cell Nucleus - genetics; Chemotherapy; Cytoplasm; Cytoplasm - genetics; Differentiation (biology); Gene expression; Gene Expression Regulation, Leukemic - genetics; Gene mutations; Genetic aspects; Genomes; Health aspects; HL-60 Cells; Humans; Leukemia; Leukemia research; Leukemia, Myeloid, Acute - genetics; Life Sciences; Localization; Male; Mice; Mice, Inbred NOD; Mice, SCID; Microenvironments; mRNA; Mutants; Mutation; Mutation - genetics; Myeloid leukemia; Nuclear Proteins - genetics; Nuclear transport; Nucleophosmin; Nucleoproteins; Pathogenesis; Ribonucleic acid; RNA; RNA, Long Noncoding - genetics; RNA, Messenger - genetics; Tumor Microenvironment - genetics; Tumors; France
• ISSN: 0887-6924; 1476-5551; 1476-5551
• DOI: 10.1038/s41375-021-01307-0

The most frequent genetic alteration in acute myeloid leukemia (AML) is the mutation of nucleophosmin 1 (NPM1). Yet, its downstream oncogenic routes are not fully understood. Here, we report the identification of one long noncoding RNA (lncRNA) overexpressed in NPM1-mutated AML patients (named LONA) whose intracellular localization inversely reflects that of NPM1. While NPM1 is nuclear and LONA cytoplasmic in wild-type NPM1 AML cells, LONA becomes nuclear as mutant NPM1 moves toward the cytoplasm. Gain or loss of function combined with a genome-wide RNA-seq search identified a set of LONA mRNA targets encoding proteins involved in myeloid cell differentiation (including THSB1, MAFB, and ASB2) and interaction with its microenvironment. Consistently, LONA overexpression in mutant NPM1 established cell lines and primary AML cells exerts an anti-myeloid differentiation effect, whilst it exerts an opposite pro-myeloid differentiation effect in a wild type NPM1 setting. In vivo, LONA overexpression acts as an oncogenic lncRNA reducing the survival of mice transplanted with AML cells and rendering AML tumors more resistant to AraC chemotherapy.These data indicate that mutation-dependent nuclear export of NPM1 leads to nuclear retention and consequent oncogenic functions of the overexpressed lncRNA LONA, thus uncovering a novel NPM1 mutation-dependent pathway in AML pathogenesis.